Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
Novome Biotechnologies, South San Francisco, CA, USA.
Nature. 2018 May;557(7705):434-438. doi: 10.1038/s41586-018-0092-4. Epub 2018 May 9.
The dense microbial ecosystem in the gut is intimately connected to numerous facets of human biology, and manipulation of the gut microbiota has broad implications for human health. In the absence of profound perturbation, the bacterial strains that reside within an individual are mostly stable over time . By contrast, the fate of exogenous commensal and probiotic strains applied to an established microbiota is variable, generally unpredictable and greatly influenced by the background microbiota. Therefore, analysis of the factors that govern strain engraftment and abundance is of critical importance to the emerging field of microbiome reprogramming. Here we generate an exclusive metabolic niche in mice via administration of a marine polysaccharide, porphyran, and an exogenous Bacteroides strain harbouring a rare gene cluster for porphyran utilization. Privileged nutrient access enables reliable engraftment of the exogenous strain at predictable abundances in mice harbouring diverse communities of gut microbes. This targeted dietary support is sufficient to overcome priority exclusion by an isogenic strain , and enables strain replacement. We demonstrate transfer of the 60-kb porphyran utilization locus into a naive strain of Bacteroides, and show finely tuned control of strain abundance in the mouse gut across multiple orders of magnitude by varying porphyran dosage. Finally, we show that this system enables the introduction of a new strain into the colonic crypt ecosystem. These data highlight the influence of nutrient availability in shaping microbiota membership, expand the ability to perform a broad spectrum of investigations in the context of a complex microbiota, and have implications for cell-based therapeutic strategies in the gut.
肠道中密集的微生物生态系统与人类生物学的众多方面密切相关，而对肠道微生物群的操纵对人类健康具有广泛的影响。在没有深刻干扰的情况下，个体内部存在的细菌菌株在时间上大多是稳定的。相比之下，应用于已建立的微生物群的外源性共生菌和益生菌菌株的命运是可变的，通常是不可预测的，并且受到背景微生物群的极大影响。因此，分析控制菌株定植和丰度的因素对于新兴的微生物组重编程领域至关重要。在这里，我们通过给老鼠服用一种海洋多糖——褐藻胶和一种含有罕见褐藻胶利用基因簇的外源性拟杆菌菌株来在老鼠体内产生一个独特的代谢生态位。优先营养物质的获取使外源性菌株能够可靠地定植，并以可预测的丰度定植在具有不同肠道微生物群落的老鼠体内。这种有针对性的饮食支持足以克服同基因菌株的优先排斥，并实现菌株替换。我们将 60kb 的褐藻胶利用基因座转移到一种新的拟杆菌菌株中，并通过改变褐藻胶的剂量，在小鼠肠道中对菌株丰度进行多数量级的精细调控。最后，我们表明该系统能够将新菌株引入结肠隐窝生态系统。这些数据突出了营养物质可用性在塑造微生物群成员中的影响，扩展了在复杂微生物群背景下进行广泛研究的能力，并对肠道中的基于细胞的治疗策略具有重要意义。
